Assignment of "Diastolic Dysfunction and Pauci-inflammatory Acute Exacerbations of Chronic Obstructive Pulmonary Disease"

“慢性阻塞性肺疾病的舒张功能障碍和少发性炎症急性加重”作业

• 批准号: 9163363
• 负责人: Surya P. Bhatt
• 金额: $ 19.48万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9163363
• 关键词: Accounting; Acute; Admission activity; Adrenal Cortex Hormones; Algorithms; Antibiotics; Arrhythmia; Atherosclerosis; Bacterial Infections; Biological Markers; Biometry; Bronchodilator Agents; C-reactive protein; Cardiac; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Clinical Sciences; Clinical Trials Design; Collaborations; Comorbidity; Complement; Complex; Congestive; Coronary; Coughing; Development; Development Plans; Disease; Dyspnea; EKG P Wave; Echocardiography; Electrocardiogram; Enrollment; Environmental Pollutants; Epidemiology; Etiology; Evaluation; Event; Exhalation; Exposure to; Fostering; Frequencies; Functional disorder; Funding; Future; Glycine; Goals; Health Care Costs; Heart; Heart Atrium; Hospitalization; Infection; Inflammatory; Injury; Inspiratory Capacity; Interleukin-6; Intervention; Ischemia; K-Series Research Career Programs; Lead; Left; Length of Stay; Lung; Mass Spectrum Analysis; Master' s Degree; Measures; Morbidity - disease rate; Myocardial Ischemia; Outcome; Pathway interactions; Patients; Phase; Phenotype; Pollution; Prevalence; Production; Proline; Prospective Studies; Proteomics; Pulmonary Edema; Recovery; Research; Research Personnel; Research Proposals; Respiratory Tract Infections; Risk Factors; Serum; Serum Markers; Spirometry; Sputum; Steroids; Stretching; Supraventricular Arrhythmia; Techniques; Testing; Therapeutic Intervention; Time; Training; Translational Research; Ultrasonography; United States; Ventricular; Ventricular Arrhythmia; Virus Diseases; abstracting; base; cardiovascular visualization; career; career development; cost; indexing; insight; mortality; novel; novel therapeutic intervention; novel therapeutics; patient population; pollutant; skills; targeted treatment

Project Summary/ Abstract Acute exacerbations account for the majority of the chronic obstructive pulmonary disease (COPD)- related morbidity, mortality and costs. Though many exacerbations are triggered by bacterial or viral infections or exposure to airborne pollutants and result in marked lung inflammation, a significant number occur without a clear precipitating cause and in the absence of pulmonary or systemic inflammation (pauci-inflammatory), suggesting an alternative pathophysiology. This may in part explain why current therapies targeting lung inflammation have only a modest effect on the rate of exacerbations and their outcomes even when used in combination. We and others have shown significant interactions between the lung and the heart in COPD, with accelerated atherosclerosis, arrhythmias, and a high frequency of diastolic dysfunction which may each cause or contribute to the development of acute exacerbations. This may be particularly relevant for diastolic dysfunction which may not only lead to overt pulmonary edema but can also cause subtle pulmonary congestion leading to bronchial hyper-reactivity. The prevalence, risk factors, mechanisms and consequences of diastolic dysfunction in this patient population remain unknown. We hypothesize that a subset of pauci- inflammatory acute exacerbations are due to diastolic dysfunction resulting from cardiac ischemia, cardiac arrhythmias and/or lung hyperinflation. These “congestive” exacerbations have a different clinical and inflammatory profile compared with episodes triggered by airway infection or exposure to pollution, and would therefore be expected to respond to a very different treatment algorithm. It is further hypothesized that that diastolic dysfunction in acute exacerbations is caused by subclinical coronary ischemia, cardiac arrhythmias, and/or dynamic lung hyperinflation. We propose a prospective study to answer these high impact questions by determining the frequency of diastolic dysfunction in acute pauci-inflammatory exacerbations of COPD, its clinical implications and underlying mechanisms. We will prospectively enroll patients hospitalized for acute exacerbations of COPD and test our hypothesis with the following three specific aims. Aim 1 of this application will be to assess whether diastolic dysfunction is the primary cause of the pauci-inflammatory phenotype of exacerbations of COPD by evaluation of diastolic dysfunction and pulmonary and systemic inflammation during acute exacerbation, as well as in stable phase after recovery. The goal of Aim 2 is to evaluate the clinical implications of diastolic dysfunction by comparing the length of hospital stay, time to next exacerbation and overall frequency of exacerbations in patients with and without diastolic dysfunction in the year following their index admission. In Aim 3, we will evaluate potential mechanisms underlying diastolic dysfunction by assessing coronary ischemia and surrogates for cardiac arrhythmias, as well as lung hyperinflation during the acute event and after recovery. The results of our study will potentially identify a novel mechanism of exacerbations by defining a congestive phenotype. I will utilize this proposal to acquire additional skills in advanced echocardiographic techniques to further study the complex heart-lung interrelationships in COPD; gain a fundamental understanding of the most up-to-date mass spectrometry techniques and their applications to proteomics of the lung in COPD; as well as obtain a Master’s degree in Clinical and Translational Sciences to foster an independent career in translational research and clinical trial design. The aims of this research proposal and career development plan are possible through the active collaboration of Dr. Edwin Blalock, a leader in neutrophilic inflammation in COPD and Dr. Mark Dransfield, a leading investigator in COPD with a special focus on exacerbations and cardiovascular comorbidity. The opportunities created by this Career Development Award will provide me with a clearly delineated path to acquire expertise and develop a research niche, compete successfully for independent funding for translational and clinical research in the field of COPD and cardiovascular disease, especially as it pertains to acute exacerbations. My ultimate goal is to identify novel etio-pathogenic mechanisms and new therapies for acute exacerbations, with a special focus on the complex heart-lung interactions in this disease.

项目摘要/摘要 急性加重说明了大多数慢性阻塞性肺疾病（COPD） - 相关的发病率，死亡率和成本。尽管许多恶化是由细菌或病毒感染触发的 或暴露于空气传播污染物并导致明显的肺部感染，大量发生的数量没有 明确的降水原因以及没有肺或全身注射（Pauci-Inflammatory）， 提出另一种病理生理学。这可能部分解释了为什么当前针对肺的疗法 即使在 组合。 我们和其他人在COPD中显示了肺和心脏之间的显着相互作用， 加速动脉粥样硬化，心律不齐和舒张功能障碍的高频 或为急性加重的发展做出贡献。这可能与舒张期特别重要 功能障碍不仅可能导致明显的肺水肿，还会引起微妙的肺 充血导致支气管高反应性。患病率，风险因素，机制和后果 该患者人群中的舒张功能障碍仍然未知。我们假设一部分Pauci- 炎症性急性加重是由于心脏缺血，心脏的舒张功能障碍引起的 心律不齐和/或肺部过滤。这些“充血”加剧具有不同的临床和 与气道感染或暴露于污染触发的发作相比 因此，期望对一种非常不同的治疗算法做出反应。进一步假设 急性加重中的舒张功能障碍是由亚临床冠状动脉缺血，心律不齐，心律失常引起的 和/或动态肺部过滤。我们提出了一项前瞻性研究，以回答这些高影响问题 确定COPD的急性炎症性加剧症状舒张功能障碍的频率 临床意义和潜在机制。 我们可能会招募患者因COPD急性加重而住院的患者，并测试我们的 假设以下三个特定目标。本应用的目标1将是评估是否舒张 功能障碍是通过评估加重COPD的PAUCI炎症表型的主要原因 急性加重期间的舒张功能障碍，肺和全身炎症 恢复后稳定阶段。目标2的目的是通过通过 比较住院时间，下一次加重的时间以及加重的总体频率 入院指数后的一年和没有舒张功能障碍的患者。在AIM 3中，我们将 通过评估冠状动脉缺血和 急性事件和恢复后的心律不齐以及肺部过度充气的替代。 我们研究的结果将有可能通过定义充血来确定加重的新机制 表型。 我将利用此建议来获得高级超声心动图技术的其他技能 进一步研究COPD中复杂的心肺相互关系；对最大的理解 最新的质谱技术及其在COPD中肺部蛋白质组学中的应用；也 获得临床和转化科学硕士学位，以培养转化的独立职业 研究与临床试验设计。这项研究建议和职业发展计划的目的是 通过COPD中性粒细胞炎症的领导者Edwin Black博士的积极合作和博士 Mark Dransfield，COPD领先的调查员，特别关注加重和心血管 合并症。该职业发展奖创建的机会将为我提供一个明显的 划定获得专业知识和开发研究利基的途径，成功地竞争独立 在COPD和心血管疾病领域进行翻译和临床研究的资金，尤其是 与急性加重有关。我的最终目标是确定新型的etio致病机制和新的 急性加重的疗法，特别关注该疾病中复杂的心肺相互作用。